Focal Segmental Glomerulosclerosis (FSGS)

TAUHID AHMED BHUIYAN, PHARMDPHARMACY PRACTICE RESIDENCY

(PGY-1) , R2

Topic Review and Case PresentationFocal Segmental

Glomerulosclerosis (FSGS)

King Faisal Specialist Hospital and Research Center (KFSHRC) is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. (UAN# 0833-0000-14-064-L01-P, 0833-0000-14-064-L01-T)

http://www.acpe-accredit.org/pdfwebtool/Common/images/logo/ACPE_489_469.jpg

ObjectivesTo provide a general overview of FSGS

To identify clinical presentations of FSGS

Outline possible evidenced-based management strategies of FSGS

Analyze a patient case of FSGS

I do not have financial relationship and no actual or potential conflict of interest in relation to this activity

BackgroundDisease “entity” defined by findings on the kidney

biopsy

Characterized by scarring or hardening of glomeruli Affect alternation of normal glomerular structure and function

It is a major cause of idiopathic steroid-resistant nephrotic syndrome in children and adults

Unlike minimal change disease, FSGS often progress to end-state renal disease (ESRD)

EpidemiologyFrequency:

Adults > children

Prevalence in adults: ≥45 years old

In US, >5400 patients are diagnosed with FSGS each year and ~20K patients are currently living with ESRD due to FSGS

In children The 2nd leading cause of renal failure Accounts for 15%-20% of cases with nephrotic syndrome Most common cause of steroid-resistant nephrotic syndrome

FSGS Facts. Accessed: February 22, 2014. Available at: http://nephcure.org/livingwithkidneydisease/understanding-fsgs/fsgs-

facts/

In Kingdom of Saudi Arabia

In Saudi registry (2000): 1294 renal biopsies were obtain from six large referral

hospital Glomerulonephritis (GN) accounted for ~73% of total

biopsy FSGS was the most common form found (~21.3%)

Nawaz et al. conducted a five-year, single center, retrospective study Primary GN accounted for 55.1% of all renal biopsies Most common histological lesion was focal segmental

glomerulosclerosis (FSGS) (27.6%)

Huraib S., et al. Saudi J Kidney Dis Transpl. 2000;11(3):434-41

Nawaz Z., et al. Saudi J Kidney Dis Transpl. 2013; 24(6):1265-70

DefinitionDescribed as:

“Segmental increase of mesangial matrix with obliteration of the capillaries, sclerosis, hyalinosis, foam cells, and segmental scarring, and adhesion between the glomerular tuft and Bowman’s capsule”

Based on appearance of the kidney tissue on biopsy:

F S G S

Focal: some of the glomeruli involved

(as opposed to diffuse)

Segmental: part of the glomerulus

involved (as opposed to

global)

Glomerulus

Scarring/hardenin

g

KDIGO Clinical Practice Guideline for Glomerulonephritis 2012

Normal vs. Pathological

Anatomy of Glomerulus

http://what-when-how.com/acp-medicine/glomerular-diseases-part-4

Classification

• When no underlying cause is found

• Usually, presents with acute or subacute nephrotic syndrome

Primary/Idiopathic

• When an underlying cause is identified (see etiology)

• Usually, presents with kidney failure

• Proteinuria is non-nephrotic range

Secondary

Gbadegsin R., et al. Pediatr Nephrol. 2011 Jul;26(7):1001-15

Factors that Determine Glomerular Filtration

Specialized fenestrated

endothelial cells

Glomerular basement

membrane (GBM)

Glomerular epithelial cells

(podocytes)


EtiologyPrimary/Idiopathic

FSGS

Hereditary diseases Sickle cell disease

Viral infections HCV, HIV Cytomegalovirus Epstein-Barr virus Parvovirus B19

Drugs/Toxic agents Interferon-α, pamidronate,

lithium, gold, heroin (IV)

Ischemia Renal artery stenosis Hypertensive kidney disease Calcineurin inhibitors (CNIs)

nephrotoxicity Acute and chronic renal

allograft rejection Cholesterol crystal embolism Cyanotic congenital heart

disease


Pathophysiology

Reidy K., et al. Pediatr Nephrol. 2007;22:350-54

Key factor in the pathogenesis “Podocyte damage and loss”

Injury to podocyte occurs by 4 major mechanisms:1. Alteration of the components of the slit diaphragm or

interference with its structure2. Dysregulation of the actin cytoskeleton3. Alteration of the glomerular basement membrane or its

interactions with the podocyte4. Alteration of the negative surface charge of the podocyte

Pathophysiology Cont.


1

2

3

4

Pathological Variants Tip variant

Involving the part of the glomerulus near the origin of the proximal tubule

Perihilar variant Sclerosis of the vascular pole

Cellular variant Hypercellularity of the capillary space

Collapsing variant With ≥1 glomeruli with global or segmental collapse

Reidy K., et al. Pediatr Nephrol. 2007;22:350-54

Progress more rapidly to ESRD

Clinical Presentation>70% of patients present with signs and symptoms of

nephrotic syndrome

Nephrotic range (>3.5 g/d) proteinuria Generalized edema Hypertension Hypoalbuminemia Hyperlipidemia Microscopic hematuria

Renal failure

Pleural effusion and ascites may present

Pericardial effusion (rare)Stephen M. Korbet J Am Soc Nephrol 2012;23:1769-77

Nephrotic Syndrome in FSGS

Classification Reduction of proteinuria (g/d)

Complete remission <0.3

Partial remission 0.3-3.5

Relapse >3.5

Steroid-dependent Two relapses during 2 weeks of completing steroid therapy

Steroid-resistant Persistence of proteinuria despite prednisone therapy for >4 months


Prognosis Inadequate response

Time from the onset of gross proteinuria to ESRD is 6-8 years

“Degree of proteinuria”– key factor determining renal survival

Non-nephrotic proteinuria: <15% progress to ESRD over the course of 10 years

Nephrotic range proteinuria: ≥50% progress to ESRD over 5-10 years Massive proteinuria (>10-14 g/d): malignant form, resulting in ESRD by

2-3 years

In general, males are 1.5-2 times more likely to progress to ESRD than affected females

Prevalence rate is much higher in blacks than whitesStephen M. Korbet J Am Soc Nephrol 2012;23:1769-77

Diagnostic Workup Patient’s past medical history

Laboratory investigations Urine analysis (UA), renal profile, serology,

autoimmune screen, toxicology, etc.

Imaging studies Ultrasound (US) of kidney

Renal biopsy (GOLD STANDARD)

Management

Goals of Therapy

Short term: To achieve complete remission of proteinuria To preserve kidney function

Long term: Prevent relapses Slowing the progression to ESRD

Pharmacological Management

KDIGO Guideline (Level of Evidence Classification)


Treatment Approaches

Stephen M. Korbet J Am Soc Nephrol 2012;23:1769-77

Conservative management

Initial immunosuppressive therapy

Treatment of relapsing FSGS

Treatment of steroid-resistant (SR) FSGS

Conservative Approach

Initially for first 6 months (both for nephrotic + non-nephrotic) Optimal blood pressure control Use of angiotensin converting enzyme (ACE)

inhibitors or angiotensin-receptor blockers (ARBs)

Goal: Slow rate of progression Provide better renal survival


Initial Immunosuppressive Therapy

Two pharmacological options:

Corticosteroids

Mycophenolate mofetil (MMF)/CNIs— steroid-sparing alternatives

CorticosteroidsMainstay of treatment for idiopathic FSGS with nephrotic

syndrome

Mechanism of action: Not fully understood, however, possibly through suppression of T-

lymphocyte mediated response

Treatment regimen: Prednisone oral:

1 mg/kg/day (max 80 mg/day) or alternate-day of 2 mg/kg (up to 120 mg) for at least 4 weeks

Taper (complete remission): reduce dose by 10mg per 2 weeks down to 0.15 mg/kg/d, then taper dose every 2–4 weeks by 2.5 mg

Remission rate: Complete: 28% to 74% Partial: 0% to 50%


Adverse EffectsCardiovascular

Sodium retention Fluid retention Potassium depletion Hypertension

Endocrine Carbohydrate intolerance and

diabetes mellitus Cushingoid features Growth retardation Menstrual irregularities

Neurologic Altered mood Headaches

Musculoskeletal Osteoporosis Muscle weakness Myopathy

Dermatologic Increased bruising Skin thinning Acne

Gastrointestinal Peptic ulceration Pancreatitis

Rowe I., et al. Primer on Transplantation, 3rd edition

MMF

Application: High-dose steroids is a concern (e.g. diabetes, morbid

obesity)

Nayagam et al. in a randomized prospective trial MMF 1 g twice daily for 6 months + low-dose (0.5

mg/kg/d) prednisone for 2–3 months (n =17) VS. High dose (1 mg/kg/d) for 3–6 monthsMMF vs. high dose prednisone Remission rate: 70% vs. 69% Time to remission: 6 weeks vs. 10 weeks Relapse: 23% vs. 18%


Adverse Effects

Diarrhea

Upper gastrointestinal disturbances

Myelosuppression leukopenia and anemia

Cardiovascular Hypertension, peripheral edema


KDIGO Recommendations Corticosteroid and Immunosuppressive for idiopathic

FSGS associated with clinical features of nephrotic syndrome (1C)

Initial high dose corticosteroids for a minimum of 4 weeks; maintain to a maximum of 16 weeks or complete remission (2D)

Corticosteroids be tapered slowly over a period of 6 months after achieving complete remission (2D)

CNIs be considered as first-line therapy for patients with relative contraindications or intolerance to high-dose corticosteroids (2D)


Initial Management

Relapsing FSGS

Occurs in 25%–36% of patients after a complete remission and in >50% of patients with partial remission

Average time to relapse after a complete remission ranges from 20 to 36 months

Treatment is similar to relapsing minimal-change disease (MCD) per KDIGO recommendations Course of steroid, CNIs, or cytotoxic agents

(cyclophosphamide, chlorambucil, or MMF)

Rowe I., et al. Primer on Transplantation, 3rd editionKDIGO Clinical Practice Guideline for Glomerulonephritis

2012

Steroid-Resistant FSGSGreatest concern, significant risk for

progression to ESRD

Patient who are unresponsive to steroid therapy for >4 months

Cytotoxic therapy has poor response, ~18%-22%

Drug of choice: cyclosporine A (CSA) Response rate: ~70%


Steroid-Resistant FSGS Cont.Dosing regimen

CSA: 3–5 mg/kg/day in two divided doses (target levels 125–175 ng/ml) for at least 4-6 months (2B)

If remission, continue therapy for 1 year, then reduce CSA dose by 25% every 2 months as a slow taper (2D)

If no remission by 6 months, discontinue CSA

Tacrolimus 0.1–0.2 mg/kg/d in two divided doses (initial target levels 5–10 ng/ml) + low dose prednisone (0.15 mg/kg/d)

If remission: follow same duration as CSA


Steroid-Resistant FSGS Cont.Cattran el at. conducted the largest randomized placebo-

controlled trial of 49 steroid resistant FSGS patients, CSA group (n = 26): 3.5 mg/kg/d in two divided doses for 6 months All received low dose corticosteroid (0.15 mg/kg/d) Results:

Complete remission at 6 months: 69% (CSA group) vs. 12% (placebo) Partial remission: 57% (CSA group) vs. <5% (placebo) Average time to remission: 7 weeks [range: 1,25] However, at 78 weeks 60% of CSA group relapsed

Meyrier et al. studied nephrotoxicity of CSA using renal biopsy post 1 year of CSA therapy Result: risk of nephrotoxicity was generally seen at 11-29 months

and dose >5.5 mg/kg/d posed greatest toxicity


Adverse Effects of CNIs System Adverse effects

RenalRenal failureHyperuricemia and goutHyperkalemiaHypomagnesemia

Cardiovascular Hypertension

Endocrine Glucose intolerance and diabetes mellitus

NeurologicalHeadachesMigraineTremor

Other HirsutismGum hypertrophy


Role of Rituximab

Chimeric monoclonal antibody that inhibits CD20 mediated B lymphocyte proliferation and differentiation

Efficacy not well defined (isolated case reports)

Fernandez-Fresnedo G. et al (2009) conducted a study of 8 adult patients with idiopathic FSGS Only 2 out of 8 achieved sustained remission following rituximab

treatment

KDIGO guideline: Insufficient evidence to support the use

Patient Case

Subjective Date of Admission: 10/02/2015

CC: “generalized edema”

HPI: AY, is a 15 year old female with k/c of steroid sensitive nephrotic syndrome

(SSNS) since the age of 3 Complaining of generalized edema and nausea for 3 months; positive for

weight gain >15 kg in 4 months (cushingoid features) Denied any history of fever, chest pain, diarrhea, or abdominal pain Steroid dependent, currently on FK506 Had multiple relapses over the course of 10 years, resistant to cyclosporine Last relapse was in 2009 for which she was treated with course of steroid Renal biopsy on August 2014 showed (?) FSGS

PMHx: SSNS since the age of 3

FH/SH: Unknown

Allergy: NKA

Medications prior to admission1. Tacrolimus 2 mg PO every 12 hours2. Magnesium Oxide 800 mg PO BID3. Ranitidine 150 mg PO daily4. Ergocalciferol 800 units PO dialy 5. Enalapril 10 mg PO daily

Initial Findings Vitals (on admission):

BP: 147/101 mmHg; HR: 85 bpm; RR: 20 brth/min; O2 sat: 97% RA; Temp: 36.8

Physical Exams: No acute distress CVS: S1 + S2 + 0 Chest: clear; equal air entry with normal

breath sounds Ext: + edema, non pitting; no JVD CNS: unremarkable Abd: distended with stretch mark but no

tenderness Height: 155 cm; Weight: 115 kg (standing)

Labs

CBC:

Chemistry:

TDM: FK506 <2.1 ug/L Lipid profile (22/08/2014)

Urine analysis 3+ protein; 2+ blood; neg. for ketone, nitrate, leucocytes, culture;

0-1 hyaline cast in the urine Protein, random: 11.7 g/L; protein/creatinine, random: 10

WBC: 6.08

Hgb: 119

Hct: 0.371

MCV: 84.5

Plt: 237

BUN: 7.7 Cr: 206 K: 4.8 Na: 149 Cl: 118 CO2 20Ca: 1.67 PO4: 1.79 Mg: 0.66 Alb:

15.7ALT: 8.2 AST:

12.4

Trig: 4.97 Chol: 7.261

HDL: 1.22 LDL: 4.83

Assessment: Relapsing FSGS Acute kidney injury:

ATN vs. Relapse

Plan: Discontinue FK506 Start furosemide 80 mg

PO twice a day Renal ultrasound

Hospital MedicationsAlbumin 20% 100 mL once (2) Diuresis Furosemide 40 mg IV push once

Diuresis

Furosemide 80 mg PO BID DiuresisCholecalciferol 1000 units PO daily

Vit D supp

Magnesium Oxide 400 mg PO BID

Magnesium replacement

Omeprazole 20 mg PO every 12 h

GI prophylaxis

Tacrolimus 2 mg PO daily Nephrotic syndrome

Day 1-2S:

No acute distress

O: Patient is still edematous US: normal kidney size; mild dilatation of bilateral calices without

evidence of obstruction Autoimmune screen: negative CBC: Unremarkable Chemistry:

P: Psychiatry consult Arterial and venous mapping studies Prepare for renal replacement therapy (RRT) or possible rituximab

therapy

Na: 143 K: 3.8 Cl: 112 CO2 20 BUN: 6.8 Cr: 187

Ca: 1.78 PO4

1.61Mg 0.75 Alb:

22.2Total pro: 36.3

UOP: 500 mL

Day 3-4

Patient was asking for discharge

Doing well; ambulating; mild lower limb pitting edema

Discharge to home on 14/02/2015 (Saturday) against primary team

Hydrochlorothiazide 50 mg po daily Lasix 160 mg po in the morning and 80 mg po at lunchtime. Lisinopril 10 mg po daily Calcitriol 0.25 mcg po every other day Omeprazole 20 mg po twice a day Magnesium oxide 400 mg po twice a day

Summary

FSGS is a progressive form of glomerular kidney disease results from hardening/scarring of glomeruli

Adult male are highly susceptible for disease occurrence

Loss of podocytes is the key determinant factor in pathogenesis of the disease

Cardinal signs and symptoms of FSGS usually coincides with that of nephrotic syndrome

Summary

Prognosis of FSGS depends on degree of proteinuria

Renal biopsy is the definitive tool to diagnose FSGS

Although there is no definitive treatment till date, early steroid therapy has shown to have higher response rate for management of FSGS

For steroid resistant FSGS, cyclosporine is the drug of choice, however has higher relapse rate after the cessation of therapy

Documents

Focal Segmental Glomerulosclerosis (FSGS)